Project Summary Type 1 diabetes (T1D) is a substantial public health burden because affected individuals require lifelong insulin treatment and are at high risk for secondary comorbidities. While the etiology of T1D is not fully understood, it is generally accepted that both the development of islet autoimmunity and progression from islet autoimmunity to clinical T1D involves a complex interplay of genetic and environmental factors. Epigenetic modifications, including DNA methylation, may be markers of the effects of environmental exposures on gene expression and are likely to be crucial mechanisms involved in gene regulation. The development of preventive public health interventions is dependent on our ability to understand these mechanisms. The Diabetes Autoimmunity Study in the Young (DAISY) is a cohort of 2,547 children at high risk for T1D who have been followed for the appearance of autoimmunity and progression to T1D. We propose to study epigenetic and gene expression biomarkers in DAISY, in order to elucidate why some individuals with islet autoimmunity develop T1D (progressors), others continue to produce antibodies but do not develop T1D (maintainers), and more importantly, why some individuals revert to being autoantibody negative and do not progress to T1D (reverters). We believe the reverters represent a resilient group that may hold key information about the epigenetic and gene expression mechanisms that minimize risk of progression to T1D. We propose to follow 211 individuals who developed islet autoimmunity during DAISY follow-up, and 1) identify DNA methylation patterns before and after the onset of islet autoimmunity among reverters (n=52), progressors (n=87), and maintainers (n=72); and 2) identify gene expression changes after the onset of islet autoimmunity among reverters, maintainers, and progressors. Pathway analyses will then allow us to integrate methylation and expression patterns identified in the two aims and will inform our understanding of the relevant biology. Together, these aims will close gaps in our understanding of the islet autoimmune disease process through the identification of epigenetic and gene expression patterns that lead to islet autoantibody reversion. This research foundation will facilitate future studies aimed at identifying the upstream environmental influences on reversion. Using islet autoantibody reversion as a model of disease resolution, the proposed study has important implications for the development of public health interventions that will manipulate these environmental exposures and prevent progression from islet autoimmunity to clinical T1D.